Abstract Hippocampal sclerosis of aging (HS) is present in up to a third of brain autopsy samples of older than 90-year- olds who die with dementia. Compared to Alzheimer's disease pathology (AD), HS pathology is a much stronger predictor of dementia in the oldest old. Despite its importance, HS remains a post-mortem diagnosis due to lack of specific biomarkers that can predict the pathology during life. Most patients harboring HS pathology are misdiagnosed as Alzheimer's disease. Given the high prevalence of dementia in the oldest old, who are the fastest growing segment of our population, there is an urgent need to diagnose this important cause of dementia in this age group. In addition to the importance of accurate diagnosis for studying HS during life, we have recently identified an association between HS and clinical history of autoimmunity, thyroid disease, and thyroid antibodies. This implies HS might be a modifiable condition should it be diagnosed early. The 90+ study, one of the largest studies of dementia and its risk factors in the oldest old, provides the perfect platform to study HS as the condition becomes twice as common in the older compared to younger than 90-year-old age group. In aim 1, we will test the hypothesis that compared to AD, HS sufferers have a significant impairment of episodic memory both at mild stages of dementia and longitudinally. We will also examine the longitudinal course of these two conditions testing the hypothesis that HS sufferers have a slower rate of cognitive decline. In aim 2, using T1 and T2 MRI sequences, we will test the hypothesis that disproportionate atrophy of CA1 region of hippocampus and increased hippocampal T2 relaxation can be leveraged to diagnose HS from AD during life. We will also test the hypothesis that memory impairment in the oldest old is significantly associated with CA1 region atrophy and hippocampal T2 signal change. In aim 3, we will assess the relation between HS and the serological markers of autoimmunity and thyroid function. Through annual measurement of these markers, we will test the hypothesis that abnormal levels of serological markers of autoimmunity and thyroid disease are associated with HS and precede dementia in those with HS pathology providing a putative mechanistic link. At completion of this study, we will identify a set of neuropsychological, imaging, and serological markers that enable the diagnosis of this important and understudied cause of dementia during life. Moreover, elucidation of the relationship between HS and autoimmunity is important for disease prevention and future drug discovery. Given our unrestricted access to one of the largest and best characterized cohorts of the oldest old, we are well poised to utilize the neuropsychological data and acquire the imaging and serological data needed to study this common but poorly understood cause of dementia in this large segment of our population.